# NM_015271.5(TRIM2):c.232_233dup (p.Pro79fs)

https://sugi.bio/variant/trim2-p-pro79fs

## Summary

**TRIM2 p.Pro79fs (c.232_233dup)** is classified **Pathogenic** in TRIM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). Associated with Charcot-Marie-Tooth disease type 2R.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TRIM2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 2R.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TRIM2 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012451/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRIM2](https://sugi.bio/atlas/gene/TRIM2/) |
| Protein change (HGVS p.) | p.Pro79fs |
| Coding change (HGVS c.) | c.232_233dup |
| MANE Select transcript | [NM_015271](https://www.ncbi.nlm.nih.gov/nuccore/NM_015271) |
| Variant type | Duplication |
| Location | chr4:153275908-153275909 (GRCh38) |
| ClinVar | [VCV4734104](https://www.ncbi.nlm.nih.gov/clinvar/variation/4734104/) |

**All HGVS expressions:** `NC_000004.11:g.154197061_154197062dup`, `NC_000004.12:g.153275909_153275910dup`, `NG_041788.1:g.127792_127793dup`, `NM_001130067.2:c.151_152dup`, `NM_001302692.2:c.232_233dup`, `NM_001302693.2:c.229_230dup`, `NM_001302694.2:c.205_206dup`, `NM_001351054.2:c.205_206dup`, `NM_001351055.2:c.202_203dup`, `NM_001351056.2:c.151_152dup`, `NM_001351057.2:c.-326_-325dup`, `NM_001375488.1:c.232_233dup`, `NM_001375489.1:c.229_230dup`, `NM_001375490.1:c.232_233dup`, `NM_001375491.1:c.229_230dup`, `NM_001375512.1:c.151_152dup`, `NM_001375513.1:c.151_152dup`, `NM_001375514.1:c.151_152dup`, `NM_001375515.1:c.151_152dup`, `NM_001375516.1:c.151_152dup`, `NM_001375517.1:c.151_152dup`, `NM_001375519.1:c.232_233dup`, `NM_001375520.1:c.229_230dup`, `NM_001375522.1:c.-74-34_-74-33dup`, `NM_001375523.1:c.-74-34_-74-33dup`, `NM_001375525.1:c.-108_-107dup`, `NM_001438045.1:c.151_152dup`, `NM_001438618.1:c.232_233dup`, `NM_001438619.1:c.229_230dup`, `NM_001438620.1:c.229_230dup`, `NM_001438621.1:c.151_152dup`, `NM_001438622.1:c.151_152dup`, `NM_001438623.1:c.151_152dup`, `NM_001438624.1:c.151_152dup`, `NM_015271.5:c.232_233dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.837, GERP -0.858, phastCons 0.999 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.398, pLI 0.99998), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TRIM2** population constraint: LOEUF 0.398, pLI 0.99998, missense-Z 3.9511; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.91, 55% of residues very-high.

**6 experimental structure(s)** (PDB): [7B2R](https://www.rcsb.org/structure/7B2R), [7B96](https://www.rcsb.org/structure/7B96), [7QRV](https://www.rcsb.org/structure/7QRV), [7ZJ3](https://www.rcsb.org/structure/7ZJ3), [8A38](https://www.rcsb.org/structure/8A38), [8AMS](https://www.rcsb.org/structure/8AMS).

## What this gene does {#gene-function}

*Describes the biological roles of TRIM2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

TRIM2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | other |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-01 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 2R](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-2r/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 2R, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2R, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2R, Charcot-Marie-Tooth disease, axonal, type 2R.

## Similar variants {#similar}

Related TRIM2 variant pages (same residue, condition, or type): [TRIM2 p.Val657fs](/variant/trim2-p-val657fs), [TRIM2 p.His669fs](/variant/trim2-p-his669fs), [TRIM2 p.Ala139Val](/variant/trim2-p-ala139val), [TRIM2 p.Ala174Thr](/variant/trim2-p-ala174thr), [TRIM2 p.Ala225Ser](/variant/trim2-p-ala225ser), [TRIM2 p.Ala225Thr](/variant/trim2-p-ala225thr), [TRIM2 p.Arg166Gln](/variant/trim2-p-arg166gln), [TRIM2 p.Arg166Trp](/variant/trim2-p-arg166trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4734104). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*